Retinal homeostasis represents the sum of many immunoregulatory activities, based in both innate and adaptive immunity. This application is structured around concepts describing regulation of the presence and activity of innate immune cells in tissues; the niches in which the immune cells reside after entry into tissues; and the vascular endothelial cells that mediate the passage of cells from the circulation into the tissue. Many tissues, including retina and brain, use combinations of chemokines and chemokine receptors, especially CCL2/CCR2 and CX3CL1/CX3CR1, to facilitate entry of innate immune cells across the endothelium into the tissue. Immune cells live in, and are recruited to, niches in tissues where chemokines and cytokines maintain their presence and activity. These concepts, combined with published and preliminary results, suggested a three niche model for retina. A major retinal niche (N1) is filled by the initial seeding of the retina with microglia (MG) during retinal development. In resting retina, this population far exceeds the number of other immune cells in niche 2 (N2). We find recruited mononuclear cells in the retina of mice that express a GFP reporter in N2 using transgenic CD11c-DTR/GFP mice (CDG mice). Since they have antigen presenting function for naive, antigen-specific CD4 and CD8 T cells, we often describe them as dendritic cells (DC). Upon stimulation of the retina, whether by injury, stress or immune response, recruited cells represented by the GFP+ cells occupy N2, which can grow substantially, reaching numbers equivalent to the microglia in N1. Recent reports suggest the presence of resident progenitor cells in CNS that sustain the MG; we have designated the progenitor niche as N3. These niches have some overlap, morphologically and phenotypically, but they are distinct in some respects. For example, as an acute challenge subsides, the recruited cells in N2 are mostly lost from the retina, but the microglia in N1 largely persist. Uncertainty arises in chronic challenges to the retina, since there appears to be some replacement of MG with recruited cells, perhaps occupying N3. Casting the resident and transient occupants in a model in which they occupy different niches facilitates the formulation of questions about these cells. We propose to explore the following: 1) Can cells from N2 physically and/or functionally replace MG in N1; if so, what are the consequences for retinal health? 2) How do recruited cells get into N2; what controls their access, and how are the cells in N1 and N2 maintained in their respective niches? 3) Can the MG progenitor niche (N3) be filled with new progenitors in adult mice; will they yield fully functional MG?like cells?